Publications by authors named "Hannah Kaiser"

14 Publications

  • Page 1 of 1

Lectins enhance SARS-CoV-2 infection and influence neutralizing antibodies.

Nature 2021 Aug 31. Epub 2021 Aug 31.

Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500, Bellinzona, Switzerland.

SARS-CoV-2 infection, which involves both cell attachment and membrane fusion, relies on the ACE2 receptor that is paradoxically found at low levels in the respiratory tract, suggesting that additional mechanisms facilitating infection may exist. Here we show that C-type lectin receptors, DC-SIGN, L-SIGN and the sialic acid-binding Ig-like lectin 1 (SIGLEC1) function as attachment receptors by enhancing ACE2-mediated infection and modulating the neutralizing activity of different classes of spike-specific antibodies. Antibodies to the N-terminal domain (NTD) or to the conserved site at the base of the Receptor Binding Domain (RBD), while poorly neutralizing infection of ACE2 over-expressing cells, effectively block lectin-facilitated infection. Conversely, antibodies to the Receptor Binding Motif (RBM), while potently neutralizing infection of ACE2 over-expressing cells, poorly neutralize infection of cells expressing DC-SIGN or L-SIGN and trigger fusogenic rearrangement of the spike promoting cell-to-cell fusion. Collectively, these findings identify a lectin-dependent pathway that enhances ACE2-dependent infection by SARS-CoV-2 and reveal distinct mechanisms of neutralization by different classes of spike-specific antibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03925-1DOI Listing
August 2021

Evaluation of Cell-Based and Surrogate SARS-CoV-2 Neutralization Assays.

J Clin Microbiol 2021 09 21;59(10):e0052721. Epub 2021 Jul 21.

Vaccine and Infectious Diseases Division, Fred Hutch Cancer Research Center, Seattle, Washington, USA.

Determinants of protective immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection require the development of well-standardized, reproducible antibody assays. This need has led to the emergence of a variety of neutralization assays. Head-to-head evaluation of different SARS-CoV-2 neutralization platforms could facilitate comparisons across studies and laboratories. Five neutralization assays were compared using 40 plasma samples from convalescent individuals with mild to moderate coronavirus disease 2019 (COVID-19): four cell-based systems using either live recombinant SARS-CoV-2 or pseudotyped viral particles created with lentivirus (LV) or vesicular stomatitis virus (VSV) packaging and one surrogate enzyme-linked immunosorbent assay (ELISA)-based test that measures inhibition of the spike protein receptor binding domain (RBD) binding its receptor human angiotensin converting enzyme 2 (hACE2). Vero cells, Vero E6 cells, HEK293T cells expressing hACE2, and TZM-bl cells expressing hACE2 and transmembrane serine protease 2 were tested. All cell-based assays showed 50% neutralizing dilution (ND) geometric mean titers (GMTs) that were highly correlated (Pearson = 0.81 to 0.89) and ranged within 3.4-fold. The live virus assay and LV pseudovirus assays with HEK293T/hACE2 cells showed very similar mean titers, 141 and 178, respectively. ND titers positively correlated with plasma IgG targeting SARS-CoV-2 spike protein and RBD (= 0.63 to 0.89), but moderately correlated with nucleoprotein IgG (= 0.46 to 0.73). ND GMTs mirrored ND data and showed similar correlation between assays and with IgG concentrations. The VSV pseudovirus assay and LV pseudovirus assay with HEK293T/hACE2 cells in low- and high-throughput versions were calibrated against the WHO SARS-CoV-2 IgG standard. High concordance between the outcomes of cell-based assays with live and pseudotyped virions enables valid cross-study comparison using these platforms.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1128/JCM.00527-21DOI Listing
September 2021

Broad sarbecovirus neutralization by a human monoclonal antibody.

Nature 2021 09 19;597(7874):103-108. Epub 2021 Jul 19.

Humabs Biomed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland.

The recent emergence of SARS-CoV-2 variants of concern and the recurrent spillovers of coronaviruses into the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here we describe a human monoclonal antibody designated S2X259, which recognizes a highly conserved cryptic epitope of the receptor-binding domain and cross-reacts with spikes from all clades of sarbecovirus. S2X259 broadly neutralizes spike-mediated cell entry of SARS-CoV-2, including variants of concern (B.1.1.7, B.1.351, P.1, and B.1.427/B.1.429), as well as a wide spectrum of human and potentially zoonotic sarbecoviruses through inhibition of angiotensin-converting enzyme 2 (ACE2) binding to the receptor-binding domain. Furthermore, deep-mutational scanning and in vitro escape selection experiments demonstrate that S2X259 possesses an escape profile that is limited to a single substitution, G504D. We show that prophylactic and therapeutic administration of S2X259 protects Syrian hamsters (Mesocricetus auratus) against challenge with the prototypic SARS-CoV-2 and the B.1.351 variant of concern, which suggests that this monoclonal antibody is a promising candidate for the prevention and treatment of emergent variants and zoonotic infections. Our data reveal a key antigenic site that is targeted by broadly neutralizing antibodies and will guide the design of vaccines that are effective against all sarbecoviruses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03817-4DOI Listing
September 2021

Characterization of the Oral and Gut Microbiota in Patients with Psoriatic Diseases: A Systematic Review.

Acta Derm Venereol 2021 Jul 30;101(7):adv00512. Epub 2021 Jul 30.

Department of Dermatology and Allergy, Herlev and Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark. E-mail:

Advances in technology have led to an increased number of studies investigating the microbiome in patients with psoriasis. This systematic review examined data regarding the oral and gut microbiota in patients with psoriasis and/or psoriatic arthritis and the effect of probiotics on the microbiota and severity of psoriasis. Of 1,643 studies, 23 were included (22 observational, 1 interventional). Studies examined the microbiota using culture or 16S rRNA gene sequencing analysis. All culture-based studies identified an increased presence of oral Candida in patients with psoriasis, whereas small variations in the oral microbiota were found in a 16S rRNA gene-based study. All 16S rRNA gene sequencing based studies agreed that the gut microbiota of patients with psoriatic disease differed from that of healthy controls, but the results were heterogeneous. Probiotics were associated with a significant improvement in the severity of psoriasis, but did not change microbiota. Overall, studies lacked relevant inclusion criteria and baseline information. In conclusion, the role of the microbiota in patients with psoriasis requires further investigation using more robust methods.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2340/00015555-3882DOI Listing
July 2021

SARS-CoV-2 RBD antibodies that maximize breadth and resistance to escape.

Nature 2021 09 14;597(7874):97-102. Epub 2021 Jul 14.

Humabs BioMed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland.

An ideal therapeutic anti-SARS-CoV-2 antibody would resist viral escape, have activity against diverse sarbecoviruses, and be highly protective through viral neutralization and effector functions. Understanding how these properties relate to each other and vary across epitopes would aid the development of therapeutic antibodies and guide vaccine design. Here we comprehensively characterize escape, breadth and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD). Despite a trade-off between in vitro neutralization potency and breadth of sarbecovirus binding, we identify neutralizing antibodies with exceptional sarbecovirus breadth and a corresponding resistance to SARS-CoV-2 escape. One of these antibodies, S2H97, binds with high affinity across all sarbecovirus clades to a cryptic epitope and prophylactically protects hamsters from viral challenge. Antibodies that target the angiotensin-converting enzyme 2 (ACE2) receptor-binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency. Nevertheless, we also characterize a potent RBM antibody (S2E12) with breadth across sarbecoviruses related to SARS-CoV-2 and a high barrier to viral escape. These data highlight principles underlying variation in escape, breadth and potency among antibodies that target the RBD, and identify epitopes and features to prioritize for therapeutic development against the current and potential future pandemics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41586-021-03807-6DOI Listing
September 2021

Association between Vascular Inflammation and Inflammation in Adipose Tissue, Spleen, and Bone Marrow in Patients with Psoriasis.

Life (Basel) 2021 Apr 1;11(4). Epub 2021 Apr 1.

Department of Cardiology, Herlev and Gentofte Hospital, 2900 Hellerup, Denmark.

Psoriasis is associated with atherosclerotic cardiovascular disease (CVD) with significant overlap of inflammatory pathways. A link between vascular inflammation and inflammation in multiple adipose tissue types, spleen, and bone marrow may exist. Therefore, we investigated these associations using F-fluorodeoxyglucose positron emission tomography/computed tomography (F-FDG-PET/CT) in patients with psoriasis ( = 83) where half had established CVD. Carotid ultrasound imaging was also performed. Inflammation was measured by FDG uptake in the aorta, visceral- (VAT), subcutaneous- (SAT), and pericardial (PAT) adipose tissues, and spleen and bone marrow, respectively. Vascular inflammation was associated with FDG uptakes in all adipose tissues, including VAT (β = 0.26; < 0.001), SAT (β = 0.28; < 0.001), PAT (β = 0.24; < 0.001), spleen (β = 1.35; = 0.001), and bone marrow (β = 1.14; < 0.001). Adjustments for age, sex, body mass index, and high sensitivity C-reactive protein did not change the results. These associations were generally preserved in the patients without prior CVD. No associations were observed between vascular inflammation and carotid intima-media thickness or presence of carotid plaques, respectively. The results suggest an inflammatory link between vascular and adipose tissues, spleen, and bone marrow in patients with psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/life11040305DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065955PMC
April 2021

Structural basis for broad sarbecovirus neutralization by a human monoclonal antibody.

bioRxiv 2021 Apr 8. Epub 2021 Apr 8.

Humabs Biomed SA, a subsidiary of Vir Biotechnology, 6500 Bellinzona, Switzerland.

The recent emergence of SARS-CoV-2 variants of concern (VOC) and the recurrent spillovers of coronaviruses in the human population highlight the need for broadly neutralizing antibodies that are not affected by the ongoing antigenic drift and that can prevent or treat future zoonotic infections. Here, we describe a human monoclonal antibody (mAb), designated S2×259, recognizing a highly conserved cryptic receptor-binding domain (RBD) epitope and cross-reacting with spikes from all sarbecovirus clades. S2×259 broadly neutralizes spike-mediated entry of SARS-CoV-2 including the B.1.1.7, B.1.351, P.1 and B.1.427/B.1.429 VOC, as well as a wide spectrum of human and zoonotic sarbecoviruses through inhibition of ACE2 binding to the RBD. Furthermore, deep-mutational scanning and escape selection experiments demonstrate that S2×259 possesses a remarkably high barrier to the emergence of resistance mutants. We show that prophylactic administration of S2×259 protects Syrian hamsters against challenges with the prototypic SARS-CoV-2 and the B.1.351 variant, suggesting this mAb is a promising candidate for the prevention and treatment of emergent VOC and zoonotic infections. Our data unveil a key antigenic site targeted by broadly-neutralizing antibodies and will guide the design of pan-sarbecovirus vaccines.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.04.07.438818DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043460PMC
April 2021

Antibodies to the SARS-CoV-2 receptor-binding domain that maximize breadth and resistance to viral escape.

bioRxiv 2021 Apr 8. Epub 2021 Apr 8.

Vir Biotechnology, San Francisco, CA 94158, USA.

An ideal anti-SARS-CoV-2 antibody would resist viral escape , have activity against diverse SARS-related coronaviruses , and be highly protective through viral neutralization and effector functions . Understanding how these properties relate to each other and vary across epitopes would aid development of antibody therapeutics and guide vaccine design. Here, we comprehensively characterize escape, breadth, and potency across a panel of SARS-CoV-2 antibodies targeting the receptor-binding domain (RBD), including S309 , the parental antibody of the late-stage clinical antibody VIR-7831. We observe a tradeoff between SARS-CoV-2 neutralization potency and breadth of binding across SARS-related coronaviruses. Nevertheless, we identify several neutralizing antibodies with exceptional breadth and resistance to escape, including a new antibody (S2H97) that binds with high affinity to all SARS-related coronavirus clades via a unique RBD epitope centered on residue E516. S2H97 and other escape-resistant antibodies have high binding affinity and target functionally constrained RBD residues. We find that antibodies targeting the ACE2 receptor binding motif (RBM) typically have poor breadth and are readily escaped by mutations despite high neutralization potency, but we identify one potent RBM antibody (S2E12) with breadth across sarbecoviruses closely related to SARS-CoV-2 and with a high barrier to viral escape. These data highlight functional diversity among antibodies targeting the RBD and identify epitopes and features to prioritize for antibody and vaccine development against the current and potential future pandemics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2021.04.06.438709DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8043444PMC
April 2021

Ultrapotent human antibodies protect against SARS-CoV-2 challenge via multiple mechanisms.

Science 2020 11 24;370(6519):950-957. Epub 2020 Sep 24.

Humabs BioMed SA, a subsidiary of Vir Biotechnology, Bellinzona, Switzerland.

Efficient therapeutic options are needed to control the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that has caused more than 922,000 fatalities as of 13 September 2020. We report the isolation and characterization of two ultrapotent SARS-CoV-2 human neutralizing antibodies (S2E12 and S2M11) that protect hamsters against SARS-CoV-2 challenge. Cryo-electron microscopy structures show that S2E12 and S2M11 competitively block angiotensin-converting enzyme 2 (ACE2) attachment and that S2M11 also locks the spike in a closed conformation by recognition of a quaternary epitope spanning two adjacent receptor-binding domains. Antibody cocktails that include S2M11, S2E12, or the previously identified S309 antibody broadly neutralize a panel of circulating SARS-CoV-2 isolates and activate effector functions. Our results pave the way to implement antibody cocktails for prophylaxis or therapy, circumventing or limiting the emergence of viral escape mutants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/science.abe3354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7857395PMC
November 2020

Coronary Artery Disease Assessed by Computed Tomography in Patients with Psoriasis: A Systematic Review and Meta-Analysis.

Dermatology 2019 3;235(6):478-487. Epub 2019 Sep 3.

Department of Cardiology, Herlev and Gentofte Hospital, Hellerup, Denmark.

Background: Patients with psoriasis have an increased risk of coronary artery disease (CAD) but data on coronary calcium score (CCS) and cardiac computed tomography angiography (CCTA) are inconsistent.

Objectives: The present study quantitatively summarizes the literature data on the prevalence and burden of CAD in patients with psoriasis compared with controls using CCS and CCTA.

Methods: A systematic review and meta-analysis was conducted. The search included all studies examining CAD prevalence and burden detected by CCS with or without CCTA in patients with psoriasis without prior CAD compared with controls, between the year 2000 and May 30, 2018.

Results: Fourteen eligible studies provided data on 1,427 patients with psoriasis and 9,670 controls. Pooled data provided the estimated risk ratio (RR) of CAD and weighted mean differences of CCS in psoriasis patients versus controls. Meta-analysis of the prevalence and burden of CCS showed that patients with psoriasis had an increased risk of CAD (RR 1.14, 95% CI 1.04-1.26; p = 0.004), and for more severe CAD (CCS >100) the risk was further increased (RR 1.71, 95% CI 1.28-2.30; p < 0.001) compared with controls. Weighted mean difference for CCS was significantly higher in patients with psoriasis (12.74, 95% CI 10.70-14.78; p < 0.001). The risk of high-risk coronary plaques identified by CCTA was also significantly higher in psoriasis patients compared with controls (RR 1.77, 95% CI 1.37-2.28; p < 0.001).

Conclusions: Patients with psoriasis have a higher prevalence of subclinical CAD, a higher burden of the disease, and more high-risk coronary plaques compared with controls without psoriasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1159/000502138DOI Listing
April 2020

[Comorbidity in connection with psoriasis is more than psoriatic arthritis].

Ugeskr Laeger 2018 01;180(2)

Psoriasis is a common chronic inflammatory disease which is associated with extensive comorbidity, including psoriatic arthritis, cardiovascular and cardiometabolic disease, inflammatory bowel disease, malignancy, chronic kidney disease and depression. Clinical guidelines have been developed to target some of these comorbid diseases in patients with psoriasis and should be used by the treating physician.
View Article and Find Full Text PDF

Download full-text PDF

Source
January 2018

Age-dependent effects of UCP2 deficiency on experimental acute pancreatitis in mice.

PLoS One 2014 10;9(4):e94494. Epub 2014 Apr 10.

Division of Gastroenterology, Department of Medicine II, University Medicine Rostock, Rostock, Germany.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of acute pancreatitis (AP) for many years but experimental evidence is still limited. Uncoupling protein 2 (UCP2)-deficient mice are an accepted model of age-related oxidative stress. Here, we have analysed how UCP2 deficiency affects the severity of experimental AP in young and older mice (3 and 12 months old, respectively) triggered by up to 7 injections of the secretagogue cerulein (50 μg/kg body weight) at hourly intervals. Disease severity was assessed at time points from 3 hours to 7 days based on pancreatic histopathology, serum levels of alpha-amylase, intrapancreatic trypsin activation and levels of myeloperoxidase (MPO) in lung and pancreatic tissue. Furthermore, in vitro studies with pancreatic acini were performed. At an age of 3 months, UCP2-/- mice and wild-type (WT) C57BL/6 mice were virtually indistinguishable with respect to disease severity. In contrast, 12 months old UCP2-/- mice developed a more severe pancreatic damage than WT mice at late time points after the induction of AP (24 h and 7 days, respectively), suggesting retarded regeneration. Furthermore, a higher peak level of alpha-amylase activity and gradually increased MPO levels in pancreatic and lung tissue were observed in UCP2-/- mice. Interestingly, intrapancreatic trypsin activities (in vivo studies) and intraacinar trypsin and elastase activation in response to cerulein treatment (in vitro studies) were not enhanced but even diminished in the knockout strain. Finally, UCP2-/- mice displayed a diminished ratio of reduced and oxidized glutathione in serum but no increased ROS levels in pancreatic acini. Together, our data indicate an aggravating effect of UCP2 deficiency on the severity of experimental AP in older but not in young mice. We suggest that increased severity of AP in 12 months old UCP2-/- is caused by an imbalanced inflammatory response but is unrelated to acinar cell functions.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0094494PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3983280PMC
December 2014
-->